Development of Novel Assay Systems to Evaluate Drug Sensitivity and Resistance that Reflects Tumor Heterogeneity
Project/Area Number |
17K11669
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Pathobiological dentistry/Dental radiology
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Research Institution | Okayama University |
Principal Investigator |
Ohyama Kazumi 岡山大学, 歯学部, 博士研究員 (00253021)
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Co-Investigator(Kenkyū-buntansha) |
十川 千春 岡山大学, 医歯薬学総合研究科, 准教授 (10253022)
江口 傑徳 岡山大学, 医歯薬学総合研究科, 助教 (20457229)
奥舎 有加 岡山大学, 医歯薬学総合研究科, 助教 (50762027)
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 癌オルガノイド (Tumoroid) / 転移性頭頸部癌 / 転移性大腸癌 / 抗癌剤耐性 (治療抵抗性) / 細胞外小胞性薬剤耐性 エクソソーム / 腫瘍随伴マクロファージ(TAM)M2型 / 薬剤排出ポンプABCG2 / HSP90 / M2型腫瘍随伴マクロファージ(TAM) / TUMOROID / 細胞外小胞 / オルガノイド / 腫瘍間質 / 治療抵抗性 / 腫瘍内不均一性 / 薬剤感受性評価システム / 癌幹細胞 / がん幹細胞 / エクソソーム(細胞外小胞) / 上皮間葉転換(EMT) / セツキシマブ / 脂質代謝 / プロテオーム / 薬剤耐性 / 癌幹細胞性 / 癌 / 薬剤反応性 / 歯学 |
Outline of Final Research Achievements |
We aimed to establish a novel system to evaluate drug sensitivity and resistance that reflects intratumoral heterogeneity. We demonstrated: 1) a novel cancer exosome-driven epithelial-to-mesenchymal transition (EMT), 2) pro-tumorigenic roles of the lipid excretion pump ABCG1 and hypoxic inducible factor 1 alpha (HIF-1α) in the intratumoral hypoxic environment in three-dimensional cancer organoids, 3) a novel exosome-driven drug resistance mechanism by which antibody-based drugs such as anti-EGFR medication (cetuximab) is secreted with exosomes from resistant cancer cells, and 4) gene expression profile of cancer stem cell-like organoids and drug resistance to cisplatin.
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Academic Significance and Societal Importance of the Research Achievements |
①本研究では、エクソソームによって分子標的抗体薬(抗EGFR抗体セツキシマブ)が排出されることが解明された。同様の薬剤耐性機構が、免疫チェックポイント阻害剤でも起こると想定される。従って、エクソソーム性薬剤耐性機構は今後の医科学において重要課題を示すこととなった。②癌種に限定されない難治性癌・転移性癌の共通分子基盤として同定した細胞外HSP90およびEpCAMエクソソームは、学術的に広く汎用性の高い指標と言える。③多剤耐性遺伝子ABCG2と共発現する脂質排出ポンプABCG1がエクソソーム脂質排出に関わるという独自の発見は,今後の脂質代謝研究・エクソソーム研究を加速すると目される。
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Report
(5 results)
Research Products
(71 results)
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[Journal Article] Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer2020
Author(s)
Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki KI, Calderwood SK, Takigawa M, Okamoto K.
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Journal Title
Cancers
Volume: 12
Issue: 2
Pages: 881-881
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Knockout of MMP3 Weakens Solid Tumor Organoids and Cancer Extracellular Vesicles2020
Author(s)
Taha EA, Sogawa C, Okusha Y, Kawai H, Oo MW, Elseoudi A, Lu Y, Nagatsuka H, Kubota S, Satoh A, Okamoto K, and Eguchi T
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Journal Title
Cancers (Basel).
Volume: 12(5).
Issue: 5
Pages: 1260-1260
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Triple knockdown of CDC37, HSP90-alpha, and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer.2020
Author(s)
Ono K, Sogawa C, Kawai H, Tran MT, Taha EA, Lu Y, Oo MW, Okusha Y, Okamura H, Ibaragi S, Takigawa M, Kozaki K, Nagatsuka H, Sasaki A, Okamoto K, Calderwood SK, Eguchi T
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Journal Title
J Extracell Vesicles
Volume: in press
Issue: 1
Pages: 1769373-1769373
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer.2020
Author(s)
Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki KI, Calderwood SK, Takigawa M, Okamoto K.
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Journal Title
Cancers (Basel).
Volume: 12(4).
Issue: 4
Pages: 881-881
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3.2020
Author(s)
Sogawa C, Eguchi T, Tran MT, Ishige M, Trin K, Okusha Y, Taha EA, Lu Y, Kawai H, Sogawa N, Takigawa M, Calderwood SK, Okamoto K, Kozaki KI.
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Journal Title
Cancers (Basel).
Volume: 12(2).
Issue: 2
Pages: 523-523
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver.2020
Author(s)
Seyama M, Yoshida K, Yoshida K, Fujiwara N, Ono K, Eguchi T, Kawai H, Guo J, Weng Y, Haoze Y, Uchibe K, Ikegame M, Sasaki A, Nagatsuka H, Okamoto K, Okamura H, Ozaki K.
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Journal Title
Biochim Biophys Acta Mol Basis Dis.
Volume: 1866(6)
Issue: 6
Pages: 165731-165731
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A reporter system evaluates tumorigenesis, metastasis, β-catenin/MMP regulation, and druggability.2019
Author(s)
Sogawa C, Eguchi T, Okusha Y, Ono K, Ohyama K, Iizuka M, Kawasaki R, Hamada Y, Takigawa M, Sogawa N, Okamoto K, and Kozaki K.
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Journal Title
Tissue Engineering Part A
Volume: in press
Issue: 19-20
Pages: 1413-1425
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma.2019
Author(s)
Shimizu R, Ibaragi S, Eguchi T, Kuwajima D, Kodama S, Nishioka T, Okui T, Obata K, Takabatake K, Kawai H, Ono K, Okamoto K, Nagatsuka H, Sasaki A.
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Journal Title
International Journal of Oncology
Volume: 54(1)
Pages: 283-294
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Organoids with Cancer Stem Cell-like Properties Secrete Exosomes and HSP90 in a 3D NanoEnvironment2018
Author(s)
Eguchi Takanori, Sogawa C, Okusha Y, Uchibe K, Iinuma R, Ono K, Nakano K, Murakami J, Itoh M, Arai K, Fujiwara T, Namba Y, Murata Y, Ohyama K, Shimomura M, Okamura H, Takigawa M, Nakatsura T, Kozaki KI, Okamoto K, Calderwood SK.
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Journal Title
PLOS ONE
Volume: 13
Issue: 2
Pages: 1-34
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Depletion of lipid efflux pump ABCG1 triggers the intracellular accumulation of extracellular vesicles and reduces aggregation and tumorigenesis of metastatic cancer cells.2018
Author(s)
Namba Y, Sogawa C, Okusha Y, Kawai H, Itagaki M, Ono K, Murakami J, Aoyama E, Ohyama K, Asaumi J, Takigawa M, Okamoto K, Calderwood SK, Kozaki K, Eguchi T.
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Journal Title
Frontiers in Oncology
Volume: 8(376)
Pages: 1-16
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] 舌癌細胞株由来エクソソーム解析による頚部リンパ節転移マーカーの探索2017
Author(s)
Kisho Ono, Takanori Eguchi, Chiharu Sogawa, Jun Murakami, Toshifumi Fujiwara, Tomonari Kasai, Masaharu Seno, Jun-ichiAsaumi, Akira Sasaki, Ken-ichi Kozaki
Organizer
日本癌学会学術集会2017
Related Report
Int'l Joint Research
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